Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Organic anion transporters (OATs) and organic cation transporters (OCTs) mediate the flux of xenobiotics across the plasma membranes of epithelia. Substrates of OATs generally carry negative charge(s) whereas substrates of OCTs are cations. The goal of this study was to determine the domains and amino acid residues essential for recognition and transport of organic anions by the rat organic anion transporter, rOAT3. An rOAT3/rOCT1 chimera containing transmembrane domains 1-5 of rOAT3 and 6-12 of rOCT1 retained the specificity of rOCT1, suggesting that residues involved in substrate recognition reside within the carboxyl-terminal half of these transporters. Mutagenesis of a conserved basic amino acid residue, arginine 454 to aspartic acid (R454D), revealed that this amino acid is required for organic anion transport. The uptakes of p-aminohippurate (PAH), estrone sulfate, and ochratoxin A were approximately 10-, approximately 48-, and approximately 32-fold enhanced in oocytes expressing rOAT3 and were only approximately 2-, approximately 6-, and approximately 5-fold enhanced for R454D. Similarly, mutagenesis of the conserved lysine 370 to alanine (K370A) suggested that K370 is important for organic anion transport. Interestingly, the charge specificity of the double mutant, R454DK370A, was reversed in comparison to rOAT3-R454DK370A preferentially transported the organic cation, MPP(+), in comparison to PAH (MPP(+) uptake/PAH uptake = 3.21 for the double mutant vs 0.037 for rOAT3). These data indicate that arginine 454 and lysine 370 are essential for the anion specificity of rOAT3. The studies provide the first insights into the molecular determinants that are critical for recognition and translocation of organic anions by a member of the organic anion transporter family.
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PMID:Arginine 454 and lysine 370 are essential for the anion specificity of the organic anion transporter, rOAT3. 1133 Oct 16

We have previously shown that the multi-functional phosphoprotein osteopontin (OPN) is present in the substantia nigra (SN) and that its mRNA and protein expression are up-regulated following toxic insult. We now report the effects of the arginine-glycine-aspartic acid (RGD)-containing peptide fragment of OPN and OPN inactivation on the survival of tyrosine hydroxylase (TH) positive neurones in primary rat ventral mesencephalic (VM) cultures and in SN in the rat. Treatment of VM cultures with the fragment of OPN containing the RGD integrin binding domain did not decrease TH positive cell number, but instead the peptide fragment protected against cell loss induced by both MPP(+) and lipopolysaccharide (LPS). Incorporation of an OPN antibody into VM cultures caused a concentration-dependent loss of TH positive neurones. The OPN antibody also exacerbated MPP(+) - and LPS-induced cell loss at all concentrations tested. In the rat, administration of the RGD-containing peptide fragment of OPN protected TH positive neurones against a mechanically-induced lesion and against 6-hydroxydopamine- and LPS-induced cell loss. The protection against 6-hydroxydopamine toxicity was confirmed in a separate study using stereological analysis. By contrast, stereotaxic injection of the OPN antibody into the SN resulted in a loss of TH positive cells. These results suggest that OPN may be necessary for the survival of TH positive cells in SN but through the RGD-containing peptide fragment may also have neuroprotective properties relevant to Parkinson's disease.
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PMID:The RGD-containing peptide fragment of osteopontin protects tyrosine hydroxylase positive cells against toxic insult in primary ventral mesencephalic cultures and in the rat substantia nigra. 2062 61

Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-D-aspartic acid (NMDA) receptor in the central nervous system, and this molecular complex has been implicated in regulating neuronal excitability in several neurological disorders. Here, small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 and ZL006 were tested for neuroprotective effects in an in vitro Parkinson's disease (PD) model. We now report that IC87201 and ZL006 reduced MPP(+)-induced neuronal injury and apoptotic cell death in a dose-dependent manner in cultured cortical neurons. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased reactive oxygen species (ROS) generation, cytochrome c release, mitochondrial membrane potential (MMP) collapse, and the preserved mitochondrial complex I activity and ATP synthesis. IC87201 and ZL006 also preserved intracellular homeostasis through mitigating mitochondrial Ca(2+) uptake and promoting mitochondrial Ca(2+) buffering capacity. Moreover, treatment with IC87201 and ZL006 significantly increased the expression of Sirt3 after MPP(+) exposure, and knockdown of Sirt3 using specific targeted small interfere RNA (siRNA) partially nullified the protective effects induced by these two inhibitors. These data strongly support the hypothesis that targeting the PSD-95/nNOS interaction produces neuroprotective effects and may represent a novel class of therapeutics for PD as well as other neurological diseases where detrimental NMDA receptor signaling plays a major role.
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PMID:Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunction. 2545 82